Pyridyl-substituted benzothiophenes

ABSTRACT

The present invention provides novel pyridinyl-benzothiophenes and derivatives thereof which are useful as thromboxane A 2  (TXA 2 ) synthetase inhibitors and as such represent potent pharmacological agents.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 433,938,filed 10-12-82, now abandoned which is a continuation-in-part of Ser.No. 385,621, filed 6-8-82, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel compositions of matter. Moreparticularly, the present invention relates to substitutedbenzothiophenes and derivatives thereof. These compounds are potentthromboxane A₂ inhibitors and as such represent useful pharmacologicalagents.

Since the discovery that human platelets convert the prostaglandinendoperoxide (PGH₂) into a labile proaggregatory molecule known asthromboxane A₂ (TXA₂), researchers have sought compounds that couldselectively inhibit the biological activity of TXA₂. This end may beachieved in two different ways: the synthesis of TXA₂ can be blocked byinhibiting the TXA₂ synthetase, or a compound could be a receptor levelantagonist of TXA₂. As therapeutic agents, TXA₂ synthetase inhibitorsare more useful. See, e.g., R. Gorman, "Biological and PharmacologicalEvaluation of Thomboxane Synthetase Inhibitors," Advances inProstaglandin and Thromboxane Research, 6:417 (1980), and referencescited therein. Most important are compounds which selectively inhibitTXA₂ synthetase. Id.

PRIOR ART

A number of TXA₂ synthetase inhibitors are known. See for example thebi-heterocyclic 9,11-trideoxy-PGF-type compounds disclosed in U.S. Pat.No. 4,112,224; SQ 80,388 [1-(3-phenyl-2-propenyl)-1H-imidazole]disclosed in D. Harris, et al., Advances in Prostaglandin andThromboxane Research 6:437 (1980); pyridine and its derivatives,disclosed in T. Miyamoto, et al., Advances in Prostaglandin andThromoboxane Research, 6:443 (1980), and British patent application No.2,039,903A (abstracted in Derwent Farmdoc No. 50111C (1980)). See alsoH. Tai, et al., Advances in Prostaglandin and Thromboxane Research,6:447 (1980). Other compounds which have been disclosed as thromboxanesynthetase inhibitors include sodiump-benzyl-4(1-oxo-2-(4-chlorobenzyl)-3-phenylpropyl)phenyl phosphate,imidazoles, nordihydroguaiaretic acid, and12L-hydroperoxy-5,8,10,14-eicosatetraenoic acid (HETE). As noted in theabove named British patent specification, however, the inhibitoryactivity of these latter compounds on thromboxane synthetase is veryweak making them unsatisfactory as practically effective medicines.

SUMMARY OF THE INVENTION

Thus, the present invention particularly provides:

A compound of the formula I, wherein Z₁ is

(a) 4-pyridinyl,

(b) 3-pyridinyl, or

(c) 3-pyridinyl substituted at the 4 position by

(1) methyl,

(2) --OCH₃,

(3) --N(CH₃)₂, or

(4) --NH₂, or

(d) 3-pyridinyl substituted at the 2, 4, 5, or 6 position by chlorine;

wherein X₁ is

(a) --(CH₂)_(n) --,

(b) --C(OH)--, or

(c) --C(O)--;

wherein R₁ is hydrogen, a pharmacologically acceptable cation, (C₁ -C₁₂)alkyl, (C₃ -C₁₀) cycloalkyl, (C₇ -C₁₂) aralkyl, phenyl, phenyl mono-,di-, or trisubstituted by chloro, (C₁ -C₃) or alkyl, or phenylpara-substituted by

(a) --NHCO--R₂₅,

(b) --O--CO--R₂₆,

(c) --CO--R₂₄,

(d) --O--CO--(p--Ph)--R₂₇, or

(e) --CH═N--NH--CO--NH₂,

wherein R₂₄ is phenyl or acetamidophenyl, R₂₅ is methyl, phenyl,acetamidophenyl, benzamidophenyl, or amino, R₂₆ is methyl, phenyl, aminoor methoxy; and R₂₇ is hydrogen or acetamido, and wherein --(p--Ph) is1,4-phenylene;

wherein R₇ is

(a) hydrogen,

(b) --CH₂ OH,

(c) --COOR₁,

(d) --CH₂ N(R₄)₂,

(e) --CN

(f) --CON(R₄)₂, or

(g) --C(O)--R₄ ;

wherein R₃ is

(a) hydrogen,

(b) (C₁ -C₃)alkyl, or

(c) acyl;

wherein R₄ is

(a) hydrogen,

(b) (C₁ -C₄)alkyl, or

(c) phenyl;

wherein R₉ and R₁₂ are the same or different and are

(a) hydrogen,

(b) (C₁ -C₄)alkyl

(c) fluoro,

(d) chloro,

(e) bromo,

(f) --OCH₃, or,

(g) when taken together and attached to contiguous carbon atoms,--O--CH₂ --O--;

wherein D represents a single or a double bond;

wherein m is an integer from 0 to 4, inclusive; and wherein n is aninteger from 0 to 1, inclusive; including, pharmacologically acceptableacid addition salts thereof; and

when D represents a single bond, an enantiomer or a racemic mixture ofenantiomers thereof

The carbon atom content of various hydrocarbon-containing moieties isindicated by a prefix designating the minimum and maximum number ofcarbon atoms in the moiety, i.e., the prefix (C_(i) -C_(j)) indicates amoiety of the integer "i" to the integer "j" carbon atoms, inclusive.Thus (C₁ -C₃)alkyl refers to alkyl of one to 3 carbon atoms, inclusive,or methyl, ethyl, propyl, and isopropyl.

Examples of alkyl of one to 12 carbon atoms, inclusive, are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,undecyl, dodecyl, and isomeric forms thereof.

Examples of cycloalkyl of 3 to 10 carbon atoms, inclusive, whichincludes alkyl-substituted cycloalkyl, are cyclopropyl,2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl,2-butycyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl,2,3,4-triethylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl,2-pentylcyclopentyl, 3-tert-butylcyclopentyl, cyclohexyl,4-tert-butylcyclohexyl, 3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl,cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

Examples of aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl,2-phenethyl, 1-phenylethyl, 2-phenylpropyl, 4-phenylbutyl,3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthylmethyl).

Examples of phenyl substituted by one to 3 chloro or alkyl of one to 3carbon atoms, inclusive, are p-chlorophenyl, m-chlorophenyl,2,4-dichlorophenyl, 2,4,6-trichlorophenyl, p-tolyl, m-tolyl, o-tolyl,p-ethylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methylphenyl, and2,4-dichloro-3-methylphenyl.

The compounds of the present invention may be in the form ofpharmacologically acceptable salts. These salts are formed when R₁ is apharmacologically acceptable cation. Such cations include:pharmacologically acceptable metal cations, ammonium, amine cations, orquaternary ammonium cations.

Especially preferred metal cations are those derived from the alkalimetals, e.g., lithium, sodium, and potassium, and from the alkalineearth metals, e.g., magnesium and calcium, although cationic forms ofother metals, e.g., aluminum, zinc, and iron are within the scope ofthis invention.

Pharmacologically acceptable amine cations are those derived fromprimary, secondary, or tertiary amines. Examples of suitable amines aremethylamine, dimethylamine, trimethylamine, ethylamine, dibutylamine,triisopropylamine, N-methylhexylamine, decylamine, dodecylamine,allylamine, crotylamine, cyclopentylamine, dicyclohexylamine,benzylamine, dibenzylamine, α-phenylethylamine, β-phenylethylamine,ethylenediamine, diethylenetriamine, and the like aliphatic,cycloaliphatic, araliphatic amines containing up to and including about18 carbon atoms, as well as heterocyclic amines, e.g., piperidine,morpholine, pyrrolidine, piperzaine, and lower-alkyl derivativesthereof, e.g.,

1-methylpiperidine,

4-ethylmorpholine,

1-isopropylpyrrolidine,

2-methylpyrrolidine,

1,4-dimethylpiperazine,

2-methylpiperidine,

and the like, as well as amines containing water-solubilizing orhydrophilic groups, e.g.,

mono-, di-, and triethanolamine,

ethyldiethanolamine,

N-butylethanolamine,

2-amino-1-butanol,

2-amino-2-ethyl-1,3-propanediol,

2-amino-2-methyl-1-propanol,

tris(hydroxymethyl)aminomethane,

N-phenylethanolamine,

N-(p-tert-amylphenyl)diethanolamine,

glactamine,

N-methylglycamine,

N-methylglycosamine,

ephedrine,

phenylephrine,

epinephrine,

procaine,

and the like. Further useful amine salts are the basic amino acid salts,e.g.,

lysine and

arginine.

Examples of suitable pharmacologically acceptable quarternary ammoniumcations are

tetramethylammonium,

tetraethylammonium,

benzyltrimethylammonium,

phenyltriethylammonium, and the like.

Pharmaceutically acceptable acid addition salts are formed at theheterocyclic amine moiety and are also useful for administering thecompounds of this invention. These salts include hydrochloride,hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate,lactate, maleate, malate, succinate, tartrate, and the like. They areprepared by methods well known in the art.

The compounds of the present invention will be named herein asbenzothiophenes, using the Chemical Abstracts numbering system (seeNaming and Indexing of Chemical Substances for Chemical Abstracts duringthe Ninth Collective Period (1972-1976), a reprint of section IV fromthe Volume 76 Index Guide.)

The compounds of the present invention were tested for TXA₂ inhibitionas follows:

Rabbit aortic strips were superfused in series with Krebs solution.Thromboxane A₂ (TXA₂) was generated by mixing prostaglandin H₂ (PGH₂)with human platelet microsomes (HPM).

Potential inhibitors were tested by comparing the response of the rabbitaorta to the amount of TXA₂ produced by mixing PGH₂ and HPM without thetest compound in the reaction medium and then the amount of TXA₂produced when the test compound was added to the HPM 5 minutes beforethe HPM was mixed with PGH₂. By this means compounds which selectivelyinhibit TXA₂ synthetase are found. For a discussion of TXA₂ synthetaseinhibition testing see, e.g., R. Gorman, supra.

Using this test system, one compound5-(3-pyridinylmethyl)benzo[b]thiophene-2-carboxylic acid (Example 7),has been shown to be the most effective in inhibiting TXA₂ formation.This compound has an approximate ED₅₀ in this system of 1 ng/ml.

The novel compounds of this invention have thus been shown to be highlyactive as selective inhibitors of the thromboxane synthetase enzymesystem. Accordingly, these novel compounds are useful for administrationto mammals, including humans, whenever it is desirable medically toinhibit this enzyme system. For a discussion of the utility of TXA₂inhibitors, see, e.g., Derwent Farmdoc Nos. 18399B; 72896B; 72897B;63409B; 03755C; 03768C; and 50111C.

Thus, for example, these novel compounds are useful as antiinflammatoryagents in mammals and especially humans, and for this purpose, areadministered systemically and preferably orally. For oraladministration, a dose range of 0.05 to 50 mg per kg of human bodyweight is used to give relief from pain associated with inflammatorydisorders such as rheumatoid arthritis. They are also administeredintravenously in aggravated cases of inflammation, preferably in a doserange 0.01 to 100 μg per kg per minute until relief from pain isattained. When used for these purposes, these novel compounds causefewer and lesser undesirable side effects than do the known synthetaseinhibitors used to treat inflammation, for example, aspirin andindomethacin. When these novel compounds are administered orally, theyare formulated as tablets, capsules, or as liquid preparations, with theusual pharmaceutical carriers, binders, and the like. For intravenoususe, sterile isotonic solutions are preferred.

These compounds are useful whenever it is desired to inhibit plateletaggregation, reduce the adhesive character of platelets, and remove orprevent the formation of thrombi in mammals, including man, rabbits,dogs, and rats. For example, these compounds are useful in the treatmentand prevention of myocardial infarcts, to treat and preventpost-operative thrombosis, to promote patency of vascular graftsfollowing surgery, and to treat conditions such as atherosclerosis,arteriosclerosis, blood clotting defects due to lipemia, and otherclinical conditions in which the underlying etiology is associated withlipid imbalance or hyperlipidemia. For these purposes, these compoundsare administered systemically, e.g., intravenously, subcutaneously,intramuscularly, and in the form of sterile implants for prolongedaction. For rapid response especially in emergency situations, theintravenous route of administration is preferred. Doses in the rangeabout 0.005 to about 20 mg per kg of body weight per day are used, theexact dose depending on the age, weight, and condition of the patient oranimal, and on the frequency and route of administration.

These compounds are further useful as additives to blood, bloodproducts, blood substitutes, or other fluids which are used inartificial extracorporeal circulation or perfusion of isolated bodyportions, e.g., limbs and organs, whether attached to the original body,detached and being preserved or prepared for transplant, or attached toa new body. During these circulations and perfusions, aggregatedplatelets tend to block the blood vessels and portions of thecirculation apparatus. This blocking is avoided by the presence of thesecompounds. For this purpose, the compound is added gradually or insingle or multiple portions to the circulating blood, to the blood ofthe donor animal, to the perfused body portion, attached or detached, tothe recipient, or to two or all of these at a total steady state dose ofabout 0.001 to 10 mg per liter of circulating fluid. It is especiallyuseful to use these compounds in laboratory animals, e.g., cats, dogs,rabbits, monkeys, and rats, for these purposes in order to develop newmethods and techniques for organ and limb transplants.

The compounds of the present invention are useful in mammals, includinghumans and certain useful animals, e.g., dogs and pigs, to reduce oravoid gastrointestinal ulcer formation, and accelerate the healing ofsuch ulcers already present in the gastrointestinal tract. For thispurpose, these compounds are injected or infused intravenously,subcutaneously, or intramuscularly in an infusion dose range about 0.1μg to about 500 μg/kg of body weight per minute, or in a total dailydose by injection or infusion in the range about 0.1 to about 20 mg/kgof body weight per day, the exact dose depending on the age, weight, andcondition of the patient or animal, and on the frequency and route ofadministration.

The novel compounds are used for the purposes described above in thefree acid form, in ester form, and in the pharmacologically acceptablesalt form. When the ester form is used, the ester is any of those withinthe above definition of R₁. However, it is preferred that the ester bealkyl of one to 12 carbon atoms, inclusive. Of the alkyl esters, methyland ethyl are especially preferred for optimum absorption of thecompound by the body or experimental animal system; and straight-chainoctyl, nonyl, decyl, undecyl, and dodecyl are especially preferred forprolonged activity in the body or experimental animal.

Thromboxane synthetase converts PGH₂ (prostaglandin endoperoxide) intoTXA₂. PGH₂ is also converted to prostacyclin, PGD₂, and other compoundsby other enzymes. Thus, because the compounds of this invention inhibitthromboxane A₂ synthetase, they increase the PGH₂ substrate and thusincrease the amount of endogenous prostacyclin. Therefore, they are alsouseful for many of the pharmacological purposes for which prostacyclinis employed.

Prostacyclin and a thromboxane synthetase inhibitor have both been shownto be effective in controlling tumor cell metastasis, see, e.g., K.Honn, et al., "Thromboxane Synthetase Inhibitors and Prostacyclin CanControl Tumor Cell Metastasis," an Abstract of the Twentieth AnnualMeeting of the American Society for Cell Biology, in the Journal of CellBiology, 87:64 (1980).

Similarly, prostacyclin has been shown to be an effectiveantihypertensive agent. The compounds of the present invention are alsoused for this purpose. (See, e.g., British patent specification No.2,039,903A).

For a general discussion of the utility of TXA₂ synthetase inhibitorswhich increase endogenous prostacyclin, see, Aiken, et al. J. Pharmacol.Exp. Ther., 219:299 (1981).

The compounds of the present invention are prepared by the methodsdepicted in Chart A-K.

The benzothiophenes of the present invention are prepared by the methodof Chart A, as described more fully in Preparations 1, 2, 3, 4 and 5,and Examples 5, 7, and 8. Conversion of the formula LXXXV thiophenol tothe formula LXXXVII benzothiophene is accomplished using known methodsas described, e.g., in Y. Matsuki, et al., Nippon Kugaku Zasshi 87:186(1966) and Chapman, et al., J. Chem. Soc. 514 (1968). The formulaLXXXVII benzothiophene thus prepared is reacted with an appropriate 3-or 4- lithiopyridine compound (prepared by reacting the corresponding 3-or 4-bromopyridine compound with n-butyllithium) to yield thecorresponding formula LXXVIII compound wherein X₁ is --CH(OH)--.Reaction with thionyl chloride yields the formula LXXXIX compound. Thechloro group is removed by treatment of this compound with zinc dust inthe presence of acid (e.g., propionic acid), to yield the formula XCcompound, which is carboxylated by known means (e.g., pouring a solutionof the XC compound in an inert solvent in the presence of n-butyllithiumover crushed dry ice), to yield the formula XCI compound, which isconverted to other compounds of this invention by the methods of theprevious charts. Alternatively, as set forth in the Preparations andExamples described below, the formula LXXXVII compound is converted tothe corresponding bromomethyl compound by known means (see, e.g.,Matsuki, supra). This XCII compound is converted to the correspondingaldehyde of the formula XCIII, which is then reacted with3-lithiopyridine (as described in Example 5) to yield the formulaLXXXVIII compound which is then reacted as described above.

For compounds wherein m is one, the method of Chart B is used. An esterof the Formula XL is reduced with lithium aluminum hydride in ether ortetrahydrofuran to yield the corresponding alcohol after workup. Thisalchol is tosylated or mesylated using p-toluenesulfonyl chloride ormethanesulfonyl chloride in pyridine to yield the Formula XLII product.(Ts indicates the tosylated compound, but the compound could also bemesylated). This compound is treated with excess sodium cyanide indimethylformamide (DMF) and stirred under nitrogen at room temperaturefor 5 hr to yield the Formula XLIII cyano compound. This compound isdissolved in ethanol and treated with 25% aqueous potassium hydroxide toyield the corresponding acid. This compound is esterified by means wellknown in the art, e.g., treatment with diazomethane in methanol for themethyl ester. Pharmacologically acceptable salts are also prepared bymeans well known in the art.

Chart C depicts the synthesis of compounds of the present inventionwherein m is 2, 3, or 4. In Chart C, q is zero, one, or 2. An ester ofthe Formula L is reduced with diisobutylaluminum hydride (DIBAL) intoluene or methylene chloride at low temperature to yield, after workup,the Formula LI aldehyde. Reaction of this aldehyde with an alkoxyalkylene-triphenylphosphorane of the formula Ph₃ P═CHCH₂ -(CH₂)_(q)COOR₁₀ (wherein Ph is phenyl) yields the unsaturated ester of theFormula LII after workup. Careful reduction of this unsaturated ester byreaction with one equivalent of hydrogen over palladium-on-carbon inalcohol yields the saturated ester of the Formula LIII. The free acid ora pharmacologically acceptable salt of this ester is prepared by meanswell known in the art. The corresponding amides, phenacyl esters, andthe like are prepared by the methods depicted in e.g., U.S. Pat. Nos.4,292,445 and 4,172,206.

The dihydrobenzothiophenes are prepared as depicted in Chart D. Asolution of a formula LX benzothiophene in water is stirred with excesssodium amalgam (NaHg) for 24 hr. After workup there is obtained thecorresponding Formula LXI dihydrobenzothiophene. (See, e.g., D. T.Witiak, et al., J. Med. Chem. 14, 754 (1971).)

Reduction of the corresponding acid or ester of the formula COOR₁₀ withlithium aluminum hydride as depicted in Chart B, (XL to XLI) is used toprepare all of the corresponding alcohols within the scope of Formula I.

Chart E depicts another method for preparing the compounds of thisinvention. Reaction of the formula XCVIII compound with 3-lithiopyridine(prepared, e.g., by reaction of 3-bromopyridine with n-butyllithium)yields the formula CI compound wherein X₁ is --C(OH)--.

Chart F depicts a method for preparing chloro-pyridinyl compounds ofthis invention. The CV pyridinyl derivative is treated withm-chloroperbenzoic acid to yield the corresponding CVI N-oxide. TheN-oxide is treated with phosphorous oxychloride to yield thecorresponding chloropyridyl isomers of the formula CVII.

Substituted benzothiophenes (i.e. compounds wherein R₉ and R₁₂ are otherthan hydrogen) are prepared by the methods depicted in Charts G and H.

Chart G depicts a method for preparing methyl or methoxy substitutedbenzothiophenes. In Chart I, R₁₉ is methyl or methoxy. The formula CXVether is hydrolyzed (using hydrobromic acid for example) to yield theformula CXVI alcohol. Similarly, the formula CXV' ether ishydrogenolyzed with hydrogen over palladium on carbon catalyst to yieldthe formula CXVI alcohol. This alcohol is treated as in Chart H to yieldthe corresponding thiol, which is converted to the compounds of thisinvention by the method of Chart A.

Chart H depicts a general method for preparing the substitutedbenzothiophenes of Chart A. The R₉ and R₁₂ substitutedparamethylthiophenol starting materials of the formula CXXXI are thusprepared by conversion of an appropriate formula CXXX substituted phenolinto a thiophenol using the well established Newman-Kwart rearrangement(see, e.g., Org. Syn., 51:139 (1971)) and other related procedures. Seealso the Schonberg rearrangement by J. L. Wardell in "The Chemistry ofthe Thiol Group", ed. S. Patai, Wiley, New York, 1974, p. 163 and theKawata-Harano-Taguchi rearrangement, Chem. Pharm. Bull. (Japan), 21, 604(1973). The para-methylphenols are either commercially available or canbe prepared by methods known in the art.

Similarly, various substituted hydroxy benzaldehydes are availablecommercially or may be prepared by methods known in the art. Thehydroxybenzaldehydes are thus converted to the claimed benzothiophenesby the method of Charts H and A, as described above.

Chart I depicts a method for preparing compounds wherein X₁ is --C(O)--.A compound of the formula CXX is treated with potassium superoxide toyield the formula CXXI compound.

Hydrogenolysis of compounds wherein X₁ is --C(OH)-- is depicted in ChartJ. A compound of the formula CLV is hydrogenated using, e.g., a Parrapparatus and a palladium-on-carbon catalyst.

Compounds where Z₁ is 4-methylpyridine are prepared by converting thecorresponding 4-chloropyridine of Chart H with methyl magnesium halidesto the 4-methyl pyridine derivative according to the procedure describedin K. Thomas and D. Jerchel, in "Newer Methods of Organic Chemistry,"Vol. III., W. Foerst, ed., Academic Press, N.Y. 1964, pp 74-75.

The 4-methoxy, 4-amino, and 4-N,N-demethylamino derivatives are preparedfrom the corresponding 4-methoxy-3-bromopyridine (see T. Talik, RocznikiChem, 36:1465 (1962)), 3-bromo-4-aminopyridine (see T. Talik, RocznikiChem., 37:69 (1963)) and 3-bromo-4-dimethylaminopyridine (see J. M.Essery and K. Schofield, J. Chem. Soc., 4953 (1960)), respectively,using the procedure of Chart F (conversion of XCVIII to CI).

Preparation of various other benzothiophene derivatives within the scopeof this invention are prepared by analogous procedures well known in theart.

Certain compounds of the present invention are preferred. Thus,compounds of the formula I, wherein D denotes a double bond, X₁ is--(CH₂)_(n) -- (wherein n is zero or one, more preferably one), Z₁ is3-pyridinyl, m is zero, R₇ is COOR₁, R₁ is Na or H and R₉ and R₁₂ arehydrogen are preferred. Compounds having all these preferences are morepreferred. Thus, 5-(3-pyridinylmethyl)-benzo[b]thiophene-2-carboxylicacid is the most preferred compound of this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is seen more fully by the Examples given below.

PREPARATION 1 (p-Tolythio)acetaldehyde diethyl acetal

Refer to Chart A (conversion of LXXXV to LXXXVI).

Using the procedure described in Chapman, et al., J. Chem. Soc. 514(1968), and starting with p-methylthiophenol, the tilted compound isprepared.

PREPARATION 2 5-Methylbenzo[b]thiophene

Refer to Chart A (conversion of LXXXVI to LXXXVII).

Using the procedures of Chapman, et al., J. Chem. Soc. 514 (1968), andstarting with Preparation 1 the tilted compound is prepared, having amelting point of 37°-38° C.

PREPARATION 3 5-Bromomethylbenzo[b]thiophene

Refer to Chart A (conversion of LXXXVII to XCII).

The titled compound is prepared from the compound of Preparation 1 usingthe procedure of Y. Matsuki, et al., Nippon Kugaku Zasshi 87:186 (1966).The compound has a melting point of 97° C.

PREPARATION 4 5-Formylbenzo[b]thiophene

Refer to Chart A (conversion of XCII to XCIII).

The titled compound is obtained from the compound of Preparation 2,using the procedure of Matsuki, et al., Nippon Kasaku Zasshi 87:186(1966).

EXAMPLE 5

5-(3-Pyridinylhydroxymethyl)-benzo[b]thiophene (Formula I: Z₂ is3-pyridyl, X₂ is --CH(OH)-- and is para to the sulfur, R₇, R₉, and R₁₂are hydrogen, m is zero, and D is a double bond)

Refer to Chart A (conversion of XCIII to LXXXVI).

To a magnetically stirred solution of 3-bromopyridine (9.74 g, 61.63mmol) in 130 ml of ether, cooled in a -78° C. bath, is added over a 5min period 35.60 ml of 1.6M n-butyllithium in hexane. Stirring iscontinued at -78° C. for 1 hr. At the end of this period, the aldehydeof Preparation 4 (7.68 g, 47.41 mmol) in 60 ml of ether is added over a13 min period to the 3-lithiopyridine solution at -78° C. Stirring isthen maintained at 0° C. to -10° C. for 1 hr. The reaction is quenchedby addition of 5 ml of saturated Na₂ SO₄ solution, stirred and dilutedwith additional ether solvent. The reaction solution is dried in theanhydrous Na₂ SO₄ powder, and the solvent is removed in vacuo.Chromatography of the resulting oil with 350 g of silica gel inacetone-CH₂ Cl₂ solvent (1:1) affords 8.3 g of the titled compound as awhite solid with melting point 134.5°-136.5° C., as recrystallized fromethyl acetate-Skellysolve B (SSB--a commercial mixture of essentiallyn-hexane.)

TLC using acetone-CH₂ Cl₂ (1:6) yields an R_(f) of 0.18.

The C:H:N:S ratio is 69.43:4.48:5.86:13.41.

The mass spectrum yields an ion at 241.0556.

The NMR (CDCl₃, δ) spectrum reveals peaks at 8.60, 8.40, 7.80,7.60-7.20, 6.00, and 4.00.

PREPARATION 6 5-(3-Pyridinylchloromethyl)-benzo[b]thiophene

Refer to Chart A (conversion of LXXXVIII to LXXXIX).

To a magnetically stirred suspension of the alcohol of Example 4 (1.50g, 6.22 mmol) in 15 ml of chloroform is added 3.70 g (31.12 mmol) ofthionyl chloride. The resulting solution is refluxed for 1 hr, thencooled to room temperature and poured into 100 ml of ice cold saturatedNaHCO₃ solution. The aqueous solution is extracted with chloroform, thechloroform solution is washed with saturated NaHCO₃ solution, saturatedbrine and dried through anhydrous Na₂ SO₄. Removal of the solvent invacuo gives 1.60 g of the titled product as a golden oil. This materialis used withut further purification.

TLC using acetone-CH₂ Cl₂ (1:6) yields an R_(f) of 0.57.

The mass spectrum reveals ions at m/e 259.0241.

The NMR (CDCl₃, δ) spectrum reveals peaks at 8.70, 8.55, 7.80,7.50-7.15, and 6.20.

EXAMPLE 7

5-(3-pyridinylmethyl)-benzo[b]thiophene (Formula I: Z₂ is 3-pyridyl, X₂is --CH₂ -- and is para to the sulfur, R₇, R₉, and R₁₂ are hydrogen, mis zero)

To a magnetically stirred solution of Preparation 5 (1.50 g, 5.79 mmol)in 30 ml of chloroform is added 2.26 g of Zn dust and 0.514 g ofpropionic acid. Stirring is continued at 25° C. for 15 min. The contentsare poured into 150 ml of saturated NaHCO₃ solution and worked up in thesame manner as described above. The crude product is chromatographedwith 75 g of silica gel. Elution with EtOAc-SSB (1:1) afforded 0.850 gof the titled product as a yellow oil. Crystallization from ether-hexaneyields 0.727 g of product as a crystalline white solid with a meltingpoint 71.0°-73.5° C.

TLC using EtOAc-SSB (1:1) yields an R_(f) of 0.30.

The C:H:N ratio is 74.75:5.14:6.17:14.32.

The mass spectrum reveals ions at m/e 224.052 g.

The NMR (CDCl₃, δ) spectrum reveals peaks at 8.60, 7.90-7.10, and 4.05.

EXAMPLE 8

5-(3-Pydridinylmethyl)-benzo[b]thiophene-2-carboxylic acid, methylester; 5-(3-Pydridinylmethyl)-benzo[b]thiophene-2-carboxylic acid; and5-(3-Pydridinylmethyl)-benzo[b]thiophene-2-carboxylic acid, sodium salt(Formula I: Z₂ is 3-pyridyl, X₂ is --CH₂ -- and is para to the sulfur,R₉, and R₁₂ are hydrogen, m is zero, D is a double bond, R₇ is --COOH,--COOCH₃, or --COONa)

To a magnetically stirred solution of the compound of Example 6 (0.739g, 3.28 mmol) in 30 ml of tetrahydrofuran is added 1 equivalent of 1.6Mn-BuLi in hexane (2.05 ml). The dark solution is stirred at 25° C. for 1hr. The contents are poured into crushed dry ice in 100 ml of ether andallowed to stand at ambient temperature. 10 ml of water and 25 ml of 1NNaOH are added, and the ether layer is separated. The ether extract isfurther extracted with 20 ml of 1N NaOH. The combined basic extracts areacidified with 2N KHSO₄ to pH 5 and extracted thoroughly withchloroform. The aqueous solution is adjusted to pH 3 and againthoroughly extracted with chloroform. The combined chloroform solutionis dried with anhydrous Na₂ SO₄, and concentrated in vacuo to yield0.650 g of a foamy solid. This material is triturated with acetone,filtered, and the solid is washed with ether to yield 0.269 g of thefree acid corresponding to the titled products as a white powder,melting point 210°-212° C.

A sample of this acid in methanol is treated with etheral-CH₂ N₂ to givethe methyl ester having a melting point of 106°-108° C.

The corresponding sodium salt of this compound is prepared by treatmentof the free acid (80 mg, 0.30 mmol) in 5 ml of methanol with 1equivalent of 1N NaOH. After complete hydrolysis, the resulting solutionis freeze-dried to afford 73 mg of sodium salt with melting point ofgreater than 300° C.

TLC for the free acid in CHCl₃ MeOH-HOAc (92:7:1) yields an R_(f) of0.37; and for the ester in acetone-CH₂ Cl₂ (1:4) an R_(f) of 0.44.

The mass spectrum for the free acid reveals an ion at m/e 269.0491; forthe ester, an ion at m/e 283.0646.

The NMR (d₆ -DMSO, δ) spectrum for the free acid reveals peaks at8.70-8.40, 8.10-7.20, and 4.10. For the ester, NMR peaks are observed at8.65, 8.10, 7.90-7.20, 4.10, and 4.00.

                  TABLE I                                                         ______________________________________                                        FORMULA                                                                       ______________________________________                                         ##STR1##                                                                     ______________________________________                                                                       I                                               ##STR2##

I claim:
 1. A compound of the formula Iwherein Z₁ is (a) 4-pyridinyl,(b) 3-pyridinyl, or (c) 3-pyridinyl substituted at the 4 position by(1)methyl, (2) --OCH₃, (3) --N(CH₃)₂, or (4) --NH₂, or (d) 3-pyridinylsubstituted at the 2, 4, 5, or 6 position by chlorine; wherein X₁ is(a)--(CH₂)_(n) --, (b) --C(OH)--, or (c) --C(O)--; wherein R₇ is(a)hydrogen, (b) --CH₂ OH, or wherein R₉ and R₁₂ are the same or differentand are(a) hydrogen, (b) (C₁ -C₄)alkyl, (c) fluoro, (d) chloro, (e)bromo, (f) --OCH₃, or, (g) when taken together and attached tocontiguous carbon atoms, --O-- CH₂ --O--; wherein D represents a singleor a double bond; and wherein n is 1; including pharmacologicallyacceptable acid addition salts thereof; and when D represents a singlebond, an enantiomer or a racemic mixture of enantiomers thereof; withthe proviso that X₁ is --(CH₂)_(n) -- only when R₇ is hydrogen.
 2. Acompound of claim 1, wherein D denotes a double bond, X₁ is --(CH₂)_(n)--, m is zero, and R₉ and R₁₂ are hydrogen.
 3. A compound of claim 2,selected from the group consistingof5-(3-pyridinylhydroxymethyl)benzo[b]thiophene, and5-(3-pyridinylmethyl)benzo[b]thiophene. 4.5-(3-pyridinylhydroxymethyl)benzo[b]thiophene, a compound of claim
 3. 5.5-(3-pyridinylmethyl)benzo[b]thiophene, a compound of claim 3.